Urinary- and Plasma-Derived Exosomes Reveal a Distinct MicroRNA Signature Associated With Albuminuria in Hypertension

Abstract

Urinary albumin excretion (UAE) is a marker of cardiovascular risk and renal damage in hypertension. MicroRNAs (miRNAs) packaged into exosomes function as paracrine effectors in cell communication and the kidney is not exempt. This study aimed to state an exosomal miRNA profile/signature associated to hypertension with increased UAE and the impact of profibrotic TGF-β1 (transforming growth factor β1) on exosomes miRNA release. Therefore, exosomes samples from patients with hypertension with/without UAE were isolated and characterized. Three individual and unique small RNA libraries from each subject were prepared (total plasma, urinary, and plasma-derived exosomes) for next-generation sequencing profiling. Differentially expressed miRNAs were over-represented in Kyoto Encyclopedia of Genes and Genomes pathways, and selected miRNAs were validated by real-time quantitative polymerase chain reaction in a confirmation cohort. Thus, a signature of 29 dysregulated circulating miRNAs was identified in UAE hypertensive subjects, regulating 21 pathways. Moreover, changes in the levels of 4 exosomes-miRNAs were validated in a confirmation cohort and found associated with albuminuria. In particular miR-26a, major regulator of TGF-β signaling, was found downregulated in both type of exosomes when compared with healthy controls and to hypertension normoalbuminurics ( P <0.01). Similarly, decreased miR-26a levels were found in podocyte-derived exosomes after TGF-β stress. Our results revealed an exosomes miRNA signature associated to albuminuria in hypertension. In particular, exosomes miR-26a seemed to play a key role in the regulation of TGF-β, a relevant effector in podocyte damage. These findings support the use of exosomes miRNAs as biomarkers of cardiovascular risk progression and therapeutic tools in early kidney damage.

Exosomal and Plasma Non-Coding RNA Signature Associated with Urinary Albumin Excretion in Hypertension

“…Considerable research has been conducted over recent years into the molecular mechanisms of hypertension-associated renal pathology; however, most previous studies have focused mainly on protein-coding genes or miRNAs [ 30 , 31 , 34 , 35 , 36 ]. For example, our group revealed an exosomal miRNA signature associated with albuminuria in hypertension [ 29 ]. The lncRNA group has reached special relevance in the last years in health and diseases, but few studies have reported on the role of lncRNA in renal pathology [ 12 , 17 ].…”

“…Recent studies have demonstrated the role of exosomal ncRNAs as biomarkers in urological malignancies, chronic kidney disease, cancer or psoriasis [ 26 , 27 , 28 ]. Our group has recently found that urinary- and plasma-derived exosomes reveal a distinct miRNA signature associated with albuminuria in hypertension, reflecting changes taking place in the kidney [ 29 ]. Nevertheless, a study that analyzes the global ncRNA profile associated with early renal damage in hypertension remains largely unknown.…”

Exosomes as Intercellular Messengers in Hypertension

“…A key feature of hypertension is renal damage, and exosomes have been shown to play a role in this phenomenon. A study observed that in hypertensive patients with albuminuria, the profile of 29 plasma exosomal miRNAs was changed compared to controls [ 62 ]. These miRNAs play significant roles in the development of renal damage in hypertension.…”

Potential Applications and Functional Roles of Exosomes in Cardiometabolic Disease

“…RNA sequencing and proteomic analysis of urinary exosomes has revealed an exosome signature in the end-organ damage seen during hypertensive disease [182]. For instance, miR-26a, miR-146a and miR-596 have been associated with early kidney damage, albuminuria and a poor prognosis [182,183].…”

“…RNA sequencing and proteomic analysis of urinary exosomes has revealed an exosome signature in the end-organ damage seen during hypertensive disease [182]. For instance, miR-26a, miR-146a and miR-596 have been associated with early kidney damage, albuminuria and a poor prognosis [182,183]. Indeed, over 48 exosomal proteins and 27 exosomal miRNAs have been found to be differentially expressed between hypertensive patients and healthy controls [184,185].…”